SUMMARY Dr. Jerome Mertens is a stem cell biologist specialized in modeling human neurodegenerative diseases. During his graduate studies under the supervision of Dr. O. Brstle (University of Bonn), Jerome was extensively trained in human stem cell and reprogramming technologies, and cellular neuroscience, and he published three first-author papers on utilizing human pluripotent stem cell-derived neurons to model Alzheimer's Disease (AD). As a postdoctoral researcher at the Salk Institute under the supervision of Dr. F.H. Gage, Dr. Mertens acquired an exceptional foundation in functional neuroscience, nuclear pore biology and imaging. Being entirely dedicated to advancing human in vitro disease models, Dr. Mertens' research focus was to better understand complex human brain disorders and the process of neuronal aging. He could show that direct conversion of human fibroblasts into induced neurons (iNs) preserves signatures of cell aging, while iPSC reprogramming erases them. As a postdoctoral fellow, Dr. Mertens thus far first-authored three primary research studies in Nature, Cell Stem Cell and Molecular Psychiatry. As an independent scientist, Dr. Mertens seeks bringing together his recent findings on modeling neuronal aging, his permanent interest in AD, and powerful systems biology and bioinformatic technologies to unravel the earliest age-dependent and disease- initiating mechanisms of sporadic AD. In his Pathway to Independence Award (K99/R00) proposal, Dr. Mertens, together with his Mentor Dr. F.H. Gage, and his Co-Mentors Dr. D. Galasko, Dr. M.W. Hetzer and Dr. G. Yeo, designed a dedicated training plan in systems biology and bioinformatics, and proposes a research project that sets out to reveal the impact of cellular aging in a human model for AD. In the first aim (K99 phase) Dr. Mertens will generate both phenotypically old and rejuvenated neurons from a large set of clinically well- characterized AD patients and matched controls to better understand the impact of neuronal aging on the pathology of sporadic AD. Following an unbiased transcriptome approach, he will analyze for AD-specific gene expression profiles and work to understand which of the AD-specific gene expression signatures and related mechanisms are age-dependent and which are age-independent. In a second aim (K99/R00 phases), Dr. Mertens will study the age-related dysregulation of nucleo-cytoplasmic transport and the import receptor RanBP17, which currently emerge as major topics in aging and neurodegenerative disease research. He will measure nucleo-cytoplasmic compartmentalization in young and old AD neurons and probe for nuclear transport-based mediators of age-dependent AD pathology using live cell imaging approaches. In a third aim (R00 phase), he will generate and analyze iNs from a large set of individuals suffering from mild cognitive impairment (MCI) and pre-symptomatic middle-aged donors, in addition to clinical AD patients. His goal is to find a trajectory in the transcriptomic AD motifs to pinpoint the earliest and potentially most treatable mechanisms involved in AD pathogenesis, and to develop a biomarker for the detection of pre-disease AD.